Recombinant factor VIIa versus placebo for spontaneous intracerebral haemorrhage within 2 h of symptom onset (FASTEST): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial.

# Recombinant factor VIIa versus placebo for spontaneous intracerebral haemorrhage within 2 h of symptom onset (FASTEST): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial *The Lancet 2026* Articles Recombinant factor VIIa versus placebo for spontaneous intracerebral haemorrhage within 2 h of symptom onset (FASTEST): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial Joseph P Broderick, Andrew M Naidech, Jordan J Elm, Kazunori Toyoda, Dar Dowlatshahi, Andrew M Demchuk, Pooja Khatri, Thorsten Steiner, Philip M Bath, Heinrich J Audebert, Achala Vagal, Sohei Yoshimura, Stephan A Mayer, Lily L Wang, Noor Sabagha, J D Mocco, Carlos Molina, Richard Aviv, Emily Stinson, Syed A Quadri, Janice Carrozzella, Thien Huynh, Anh Phan, Jonathan Beall, Iris Davis, Nobuyuki Sakai, Tsuyoshi Ohta, Michiko Yokosawa, Takayuki Hara, Navdeep Sangha, Kenichi Morita, Ming Yin Dominc Tse, Christopher D Streib, Fumio Miyashita, Yolanda Silva, Yoshinari Nagakane, Tudor Gheorghiu, Chung-Huan Sun, Teruyuki Hirano, Sven Poli, Tsuyoshi Izumo, Mayumi Fukuda-Doi, Masafumi Ihara, Masatoshi Koga, Brian Buck, Kyle B Walsh, Ilana Spokovny, James C Grotta, for the FASTEST Investigators* Summary Background Recombinant factor VIIa has been shown to slow bleeding in patients with intracerebral haemorrhage Lancet 2026; 407: 773–83 (ICH), but no haemostatic agent has been shown to improve clinical outcomes. We aimed to evaluate the safety, Published Online clinical ecacy, and eect on growth of ICH and intraventricular haemorrhage (IVH) of recombinant factor VIIa in February 4, 2026 patients with acute spontaneous ICH who were most likely to benefit from treatment with this agent. https://doi.org/10.1016/ S0140-6736(26)00097-8 See Comment page 735 Methods We conducted a multicentre, prospective, double-blind, randomised, placebo-controlled, adaptive, phase 3 *Members listed in appendix 1 trial (FASTEST) at 93 sites across the USA, Japan, Canada, Spain, Germany, and the UK. Adults aged 18–80 years with (pp 3–4) a spontaneous ICH of 2–60 mL, IVH in less than two-thirds of one lateral ventricle or in less than a third of both Department of Neurology and lateral ventricles, a Glasgow Coma Scale score of at least 8, no evidence of recent ischaemic stroke or myocardial Rehabilitation Medicine infarction, no recent use of anticoagulation medication or other structural cause of ICH, and who had been treated (J P Broderick MD, with study medication within 2 h of stroke onset or last known well were eligible for inclusion. Patients were randomly N Sabagha PharmD, E Stinson MS, S A Quadri MD, assigned (1:1) by a simple randomisation scheme to either 80 μg/kg recombinant factor VIIa (intervention group) or I Davis MS), Department of an identical placebo (placebo group), administered intravenously over 2 min. All investigators and participants were Radiology (A Vagal MD, masked to allocated group assignment. The primary outcome was functional outcome at 180 days, measured by L L Wang MBBS, modified Rankin Scale (mRS; score 0–2, 3, and 4–6) and analysed by intention to treat in all randomly assigned J Carrozzella MSN), and Department of Emergency patients. The primary safety outcome was life-threatening thromboembolic events during the first 4 days, assessed in Medicine (K B Walsh MD), all randomly assigned participants. The secondary aim was change in ICH volume and ICH plus IVH volume University of Cincinnati, between baseline and 24 h of treatment administration. We performed an ordinal logistic regression, adjusted for Cincinnati, OH, USA; age, baseline ICH volume, baseline IVH volume, and pre-stroke mRS. Preplanned interim analyses, including Department of Neurology, Northwestern Medicine, adaptive sample size re-estimation and enrichment to a younger subgroup (aged ≤70 years), were also conducted. Chicago, IL, USA This trial is registered with ClinicalTrials.gov (NCT03496883) and is closed to new participants. (A M Naidech MD MSPH); Department of Public Health Findings Between Dec 3, 2021, and Oct 1, 2025, we screened 3288 patients, of whom 626 participants were randomly Sciences, Medical University of South Carolina, Charleston, SC, assigned and included in the intention-to-treat analyses: 298 (48%) in the placebo group and 328 (52%) in the USA (J J Elm PhD, A Phan MS, intervention group. 216 (35%) participants were female and 410 (65%) were male, with a mean age of 61 years (SD 12). J Beall PhD); Department of Mean time from stroke onset to administration of study drug was 100 min (SD 22). The trial met the prespecified Cerebrovascular Medicine, stopping criteria for futility at the second interim analysis. There was no dierential eect in the primary clinical National Cerebral and Cardiovascular Center, Osaka, outcome measure of mRS at 180 days between the intervention group and placebo group (adjusted common odds Japan (K Toyoda MD, ratio 1·09 [95% CI 0·79–1·51]; p=0·61). Life-threatening thromboembolic complications within 4 days occurred in S Yoshimura MD, 15 (<5%) participants in the intervention group and in four (1%) in the placebo group (relative risk 3·41 M Koga MD PhD); Division of [95% CI 1·14–10·15]; p=0·020). Compared with placebo, recombinant factor VIIa was associated with decreased growth Neurology, Department of Medicine, University of Ottawa of ICH (–3·7 mL [95% CI –5·4 to –1·9]) and of ICH plus IVH growth (–5·2 mL [–7·6 to –2·8]) between baseline and and Ottawa Hospital Research CT scan at 24 h. Institute, Ottawa, ON, Canada (D Dowlatshahi MD PhD); Interpretation Recombinant factor VIIa administered within 2 h of ICH onset slowed haematoma growth, but did Department of Clinical Neurosciences, Cumming not improve functional outcomes and showed a small increased risk of life-threatening thromboembolic School of Medicine, University complications. Further testing of recombinant factor VIIa in patients with the greatest risk of continued bleeding is of Calgary, Calgary, AB, Canada ongoing. (A M Demchuk MD); Department of Neurology, Yale School of Medicine, Funding National Institute of Neurological Diseases and Stroke, Japan Agency for Medical Research and Development, New Haven, CT, USA and Novo Nordisk. (P Khatri MD MSc); Department Articles of Neurology, Varisano Copyright © 2026 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar Klinikum Frankfurt Höchst, technologies. Frankfurt, Germany (T Steiner MD); Department of Introduction prospective population study of ICH in Greater Neurology, Heidelberg University Hospital, Intracerebral haemorrhage (ICH) is the deadliest type of Cincinnati, USA, indicated that 3–4 mL is the minimum Heidelberg, Germany stroke. Despite advances in neurocritical care over the volume reduction necessary to improve functional (T Steiner); Stroke Trials Unit, past four decades, ICH has a 30-day mortality of outcomes, as measured by the modified Rankin Scale Mental Health & Clinical approximately 40% and only 20% of survivors are (mRS).7 But this estimate does not account for the risks Neuroscience, Queens Medical Centre, University of functionally independent at 6 months.1 ICH leads to of ischaemia caused by a haemostatic agent, which could Nottingham, Nottingham, UK substantial disability and mortality in direct proportion negatively impact outcomes. Another study of (P M Bath FMedSci DSc); to the volume of bleeding. Therefore, achieving haemorrhage growth suggests that larger decreases in Department of Neurology and haemostasis is a primary therapeutic objective. The growth are necessary to change functional outcomes.8 Center for Stroke Research Berlin, Charité– primary challenge for haemostatic therapy in patients Recombinant factor VIIa slows bleeding when Universitätsmedizin Berlin, with spontaneous ICH is that almost all bleeding administered within 3 h of onset of spontaneous ICH, Berlin, Germany expansion occurs within the first 2–3 h after symptom with its greatest eect on haemorrhage growth within (H J Audebert MD); New York Medical College, Valhalla, NY, onset.2–6 For haemostatic therapies to be eective, it is 2 h.2–4 However, this agent is also associated with a USA (S A Mayer MD); crucial to treat patients who are most likely to have 5% increased risk of life-threatening thromboembolic Department of Neurosurgery, ongoing bleeding. Giving haemostatic therapies to complications compared with placebo in this patient Icahn School of Medicine, patients with ICH without active bleeding increases the group.2–4 The clinical benefit of recombinant factor VIIa Mount Sinai Health System, New York, NY, USA known risk of thromboembolic complications without seen in a phase 2b trial2 was not shown in a larger phase 3 (J D Mocco MD); Department of any potential benefit. trial.3 Post-hoc analyses of these two studies indicated Neurology, Stroke Unit, Vall The key consideration in haemostatic trials is the that recombinant factor VIIa had the greatest potential d’Hebron University Hospital, decrease in volume of ICH and intraventricular for benefit when administered within 2 h in patients Universitat Autonoma de Barcelona, Barcelona, Spain haemorrhage (IVH) expansion that is needed to improve aged 70 years and younger who did not have a large ICH (C Molina MD); Department of functional outcomes. A pooled analysis of placebo data or a large amount of IVH on baseline CT scan of the Radiology, Radiation Oncology from trials investigating recombinant factor VIIa and a head.4,9 and Medical Physics, University of Ottawa, Ottawa, ON, Canada (R Aviv MD); Department of Research in context Radiology, Mayo Clinic, Jacksonville, FL, USA Evidence before this study date investigating the hyperacute treatment of patients with (T Huynh MD); Department of Intracerebral haemorrhage (ICH), the second most common ICH. We found that recombinant factor VIIa slowed bleeding Neurosurgery, Kobe City type of stroke with the greatest disability and mortality of all but did not improve functional outcomes overall and was Medical Center General stroke subtypes, leads to substantial disability and mortality in associated with a small increase in life-threatening Hospital, Hyogo, Japan (N Sakai MD, T Ohta MD PhD); direct proportion to the volume of bleeding. We performed a thromboembolic complications. We also show that the agent’s Department of Neurosurgery, pooled analysis of previous phase 2b and phase 3 trials of haemostatic effects were concentrated in patients with the Iwate Prefectural Central recombinant factor VIIa. We also reviewed the treatment trials greatest likelihood of ongoing bleeding: those treated within Hospital, Morioka, Japan of ICH summarised in 2025 by the European Stroke 90 min or with a spot sign on CT angiography identified within (M Yokosawa MD); Department of Neurosurgery, Toranomon Organisation and European Association of Neurosurgical 2 h of onset. This study suggests that the mean volume of Hospital, Tokyo, Japan Societies guideline on stroke due to spontaneous ICH in decreased haemorrhage growth needed to improve functional (T Hara MD); Department of October, 2025. The primary challenge for haemostatic therapy outcomes for any haemostatic agent is likely to be at least Neurology, Kaiser Permanente in patients with spontaneous ICH is that almost all bleeding 6–12 mL. Our findings highlight the importance of CT Los Angeles Medical Center, Los Angeles, CA, USA expansion occurs within the first 2–3 h after symptom onset. angiography and rapid treatment in identifying efficacious (N Sangha MD); Department of Recombinant factor VIIa slows bleeding in patients with ICH, haemostatic treatments for patients with ICH. Cerebrovascular Medicine, but the clinical benefit with this agent observed in a phase 2b Niigata City General Hospital, Implications of all the available evidence Niigata, Japan trial was not subsequently shown in a larger phase 3 trial. Post- Although we report neutral results overall, this trial provides a (K Morita MD PhD); University hoc analyses of these two randomised trials indicated that roadmap for the management of two subgroups of patients of British Columbia, Vancouver, recombinant factor VIIa had its greatest potential for benefit BC, Canada with ICH. Additionally, this study provides insight into the when administered within 2 h in patients aged 70 years and (M Y Dominc Tse MBChB); amount of haemostasis needed to improve functional Department of Neurology, younger who did not have a large ICH or large amount of outcomes for patients with spontaneous ICH treated with University of Minnesota, intraventricular haemorrhage on baseline CT scan of the head. recombinant factor VIIa or other haemostatic agents. Minneapolis, MN, USA A major unanswered question is the decrease in the volume of (C D Streib MD); Division of bleeding in the brain that is needed to improve functional Neurology, Kagoshima City Hospital, Kagoshima, outcomes in patients with ICH. Kagoshima, Japan (F Miyashita MD); Hospital Added value of this study Universitari de Girona, Dr Josep To our knowledge, this multicentre, double-blind, randomised, Trueta, IDIBG, Girona, Spain placebo-controlled, phase 3 trial (FASTEST) is the largest trial to (Y Silva MD); Department of 774 Articles In addition to time from symptom onset, another who had been treated with study medication within 2 h Neurology, Kyoto Second Red biological marker of ongoing bleeding in ICH is contrast of stroke onset were eligible for inclusion. Full inclusion Cross Hospital, Kyoto, Japan (Y Nagakane MD PhD); leakage into the bed of the brain haemorrhage during and exclusion criteria are provided in appendix 1 (p 10). Department of Neurology, baseline CT angiogram of the brain, as indicated by a Data on participant sex, as well as race and ethnicity, Royal Victoria Infirmary, The spot sign.10,11 Nevertheless, the predictive value of this were self-reported. Newcastle upon Tyne Hospitals spot sign decreases over time.12 We aimed to evaluate the NHS Foundation Trust, safety, clinical ecacy, and eect on growth of ICH and Randomisation and masking Newcastle upon Tyne, UK (T Gheorghiu MD); IVH of recombinant factor VIIa in patients with acute We randomly assigned (1:1) patients to recombinant Neuroscience Institute, The spontaneous ICH who were most likely to benefit from factor VIIa (intervention group) or placebo (placebo Queen’s Medical Center, treatment with this agent. group). Any patient to receive an injection of either study Honolulu, Hawaii (C-H Sun MD); Department of Stroke and treatment was enrolled in the trial.13 Due to the high time Cerebrovascular Medicine, Methods sensitivity of the intervention, a simple randomisation Kyorin University School of Study design scheme was used in which the lowest numbered pre- Medicine, Tokyo, Japan We conducted a multicentre, prospective, double-blind, randomised kit at a site was selected. Investigators (T Hirano MD); Department of Neurology and Stroke and randomised, placebo-controlled, adaptive, phase 3 trial responsible for the central labelling of pre-randomised Hertie-Institute for Clinical (FASTEST) at 93 sites across the USA (54 sites), Japan kits had no further involvement with participant Brain Research University of (14 sites), Canada (nine sites), Spain (six sites), Germany enrolment or assessment. Tübingen, Tübingen, Germany (six sites), and the UK (four sites), including 12 mobile All investigators and participants, including those (S Poli MD); Department of Neurosurgery, Gifu University stroke units. A central review board or a site-specific assessing the outcomes and analysing the data, were Graduate School of Medicine, review board approved the trial in each participating masked to allocated group assignment throughout the Nagasaki, Japan (T Izumo MD); country and at each participating global site (Advarra study. To achieve masking, placebo appeared identical to Department of Data Science, approval number for US central institutional review the intervention agent, by use of the same solvent and National Cerebral and Cardiovascular Center, Osaka, board: Pro00041014). process (appendix 2 p 24). The interim analyses were Japan (M Fukuda-Doi MD); Because of the narrow time window to halt ongoing conducted by an unmasked statistician (JJE), in Department of Neurology, bleeding and the inability to obtain informed consent conjunction with the DSMB, who were independent of National Cerebral and from many patients with ICH due to severe brain the conduct of the trial. Cardiovascular Center, Osaka, Japan (M Ihara MD); University damage, the trial operated under exception from of Alberta, Edmonton, AB, informed consent in the USA and approved emergency Procedures Canada (B Buck MD); consent procedures in all other countries, except for All participants were assessed at baseline with the Department of Neurology, Japan, which does not currently have procedures for National Institutes of Health (NIH) Stroke Scale and a Sutter Health, Mills Peninsula Medical Center, Burlingame, CA emergency consent. Informed consent was obtained CT scan of the head. CT angiography at baseline was not USA (I Spokovny MD); Memorial from the patient or by a legally authorised representative required, but was collected when performed. All imaging Hermann Hospital-Texas either before enrolment or after enrolment when data were collected and read centrally by a single senior Medical Center, Houston, TX, USA (J C Grotta MD) emergency consent procedures were used. Although neuroradiologist at the imaging core, including ICH and there was no specific patient involvement in the design IVH volume and the presence of a spot sign on CT Correspondence to: Dr Joseph P Broderick, of the trial, exception from informed consent in the USA angiography. A baseline electrocardiogram was obtained Department of Neurology and requires focus groups and educational activities within and patients were screened for clinical signs of Rehabilitation Medicine, participating communities to educate patients about the myocardial ischaemia before study enrolment. Serum University of Cincinnati, trial and listen to their input. troponin concentrations were obtained but did not need Cincinnati, OH 45215, USA broderjp@ucmail.uc.edu An independent data and safety monitoring board to be reviewed before enrolment. See Online for appendices 1 and (DSMB) appointed by the National Institute of Neurological Participants in both treatment groups received Diseases and Stroke (NINDS) provided oversight of the management of acute ICH supported by American Heart trial. This trial is registered with ClinicalTrials.gov Association guidelines.14 Participants in the intervention (NCT03496883), EudraCT (2019-003722-25), and EU group received recombinant factor VIIa intravenously at Clinical Trials Register (2024-517383-28-00); its Universal a dose of 80 μg/kg (maximum dose 10 000 μg or 10 mg) Trial Number is U1111-1201-0087. The trial is closed to new over 2 min. Participants in the placebo group received participants. the same volume of placebo intravenously over 2 min. All study medications were administered by someone Participants licensed to give medication, such as a nurse, physician, Adults aged 18–80 years with a spontaneous ICH of at or pharmacist. least 2 mL and below 60 mL, IVH in less than Acute blood pressure management was required, with two-thirds of one lateral ventricle or in less than a third of a target systolic blood pressure of 140 mm Hg by use of both lateral ventricles, a Glasgow Coma Scale score of at intravenous medications as available within a given least 8, no evidence of recent ischaemic stroke or country. These medications included intravenous myocardial infarction within the previous 90 days, no nicardipine, diltiazem, clevidipine, labetalol, urapidil, recent use of anticoagulation medication within the enalaprilat, nitroglycerin, and nitroprusside. All previous 7 days or other structural cause of ICH, and participants were managed in an intensive care unit or Articles stroke unit after treatment. CT imaging of the brain was administration. Other prespecified endpoints are listed performed 24 h after enrolment or before surgery, if in appendix 1 (pp 29−31). surgery within 24 h of enrolment was clinically indicated. The primary safety measure was life-threatening Serum troponin concentrations were also collected 24 h thromboembolic complications during the first 4 days after treatment administration. The type of testing used after completing treatment with the assigned study drug. to measure troponin (eg, high sensitivity or conventional) Life-threatening thromboembolic complications were was recorded. Study investigators followed up defined as the development of either acute myocardial participants on days 30, 90, and 180 after enrolment. infarction, acute cerebral infarction, or acute pulmonary embolism. Secondary safety measures were these same Outcomes events within 90 days, as well as all-cause mortality at The primary outcome was the ordinal mRS 0–2, 3, 180 days. and 4–6 at 180 days, measured by the Rankin Focused Assessment Tool.15 Secondary ecacy outcome measures Statistical analysis included the ordinal mRS (0–2, 3, and 4–6) at 90 days; the We calculated the sample size using a two-sample test of ordinal mRS (all seven steps) at 180 days; the mRS 0–2 at proportions of mRS 0–2 at 90 days, including the subset 180 days; the utility-weighted mRS at 180 days; the EQ-5D of patients from the FAST trial that we planned to enrol health-related quality of life (EQ-5D) questionnaire at (14% absolute dierence in proportions between days 90 and 180; and change in ICH volume and in ICH treatment groups).3 We chose a smaller but still clinically plus IVH volume between baseline and 24 h of treatment important dierence of 10% to calculate the final sample size. With a sample size of 388 participants per group, a χ² test provided 80% power to detect a 10% absolute dierence in proportions at a two-sided α level of 0·05, 3288 patients screened for eligibility assuming a placebo proportion of mRS 0–2 of 40%. The sample size was inflated to a total of 860 participants to 2662 excluded account for 10% of participants lost to follow-up or 2304 did not meet eligibility criteria missing data, as well as the interim analysis. 357 consent not obtained 1 administrative issue at enrolment We performed the primary analysis and safety analysis on the intention-to-treat population, which included all randomly assigned patients. We compared the ordinal 626 randomly assigned values of mRS at 180 days by treatment group using an ordinal logistic regression adjusted for age, baseline ICH volume, baseline IVH volume, and pre-stroke mRS. The 298 assigned to placebo 328 assigned to recombinant factor VIIa proportionality assumption was assessed with the score 297 received study treatment in full and received study treatment in full test, with a plan to use a partial proportional odds model 1 intended dosage not received if violated. For participants who were missing a primary outcome assessment at 180 days and had not died, we 22 died 20 died applied a multiple imputation approach to model 3 lost to follow-up 4 lost to follow-up missing scores using the 90-day mRS, 30-day mRS, 3 withdrew consent 1 withdrew consent assigned treatment, and aforementioned covariates. The per-protocol analysis excluded participants who received 270 completed the study 303 completed the study less than 1·5 min of infusion of the study medication or who did not meet the key eligibility criteria. These patients included those who did not have a spontaneous 298 included in intention-to-treat analysis 328 included in intention-to-treat analysis ICH, had time from stroke onset of more than 120 min, were older than 80 years, had a baseline ICH or IVH 12 excluded from per-protocol 20 excluded from per-protocol volume outside of the eligible range, or had a baseline population population* Glasgow Coma Scale score of less than 8. 9 had time from stroke onset to 14 had time from stroke onset to administration of treatment administration of treatment The secondary and subgroup analyses of mRS outcome of >120 min of >120 min and EQ-5D at days 90 and 180 are detailed in the statistical 3 older than 80 years 2 older than 80 years analysis plan (appendix 1 pp 29−31). We analysed 6 had ICH or IVH volume outside of eligible range secondary ecacy outcomes on the intention-to-treat population in a linear, ordinal logistic, or logistic regression adjusted for age, baseline ICH volume, 286 included in per-protocol analysis 308 included in per-protocol analysis baseline IVH volume, and pre-stroke mRS. We used the Hochberg’s step-up procedure to control for multiple Figure 1: Trial profile comparisons. We assessed safety outcomes with the ICH=intracerebral haemorrhage. IVH=intraventricular haemorrhage. *Some participants were excluded for multiple reasons. Fisher’s exact test at a two-sided α level of 0·05 unadjusted 776 Articles Placebo Intervention Placebo Intervention group (n=298) group (n=328) group (n=298) group (n=328) Age, years 60 (12) 61 (12) (Continued from previous column) Age group, years Location of ICH ≤70 232 (78%) 241 (73%) Lobar 41 (14%) 35 (11%) >70 66 (22%) 87 (27%) Deep 254 (85%) 287 (88%) Sex Infratentorial 3 (1%) 6 (2%) Female 105 (35%) 111 (34%) Blood pressure, mm Hg 170/98 173/99 Male 193 (65%) 217 (66%) CT angiography performed 254 (85%) 257 (78%) Ethnicity Spot sign on CT angiography 77 (26%) 71 (22%) Hispanic or Latinx 25 (8%) 32 (10%) Study medication administered in 6 (2%) 11 (3%) Not Hispanic or Latinx 271 (91%) 296 (90%) mobile stroke unit Unknown 2 (1%) 0 ECG result Race Abnormal, clinically significant 5 (2%) 4 (1%) American Indian or Alaska Native 0 1 (<1%) Abnormal, not clinically significant 131 (44%) 145 (44%) Asian 169 (57%) 173 (53%) ECG not performed 1 (<1%) 3 (1%) Black or African American 23 (8%) 30 (9%) Normal 161 (54%) 176 (54%) Native Hawaiian or other 1 (<1%) 1 (<1%) Troponin elevation 50 (17%) 64 (20%) Pacific Islander Ultra-early haematoma growth 128 (43%) 153 (47%) Unknown or not reported 5 (2%) 5 (2%) <10 mL/h White 100 (34%) 118 (36%) Ultra-early haematoma growth, 170 (57%) 175 (53%) ≥10 mL/h Pre-stroke modified Rankin Scale score 0 281 (94%) 303 (92%) Data are mean (SD), n (%), or median (IQR). ICH=intracerebral haemorrhage. IVH=intraventricular haemorrhage. NIH=National Institutes of Health. 1 10 (3%) 17 (5%) ECG=electrocardiogram. 2 6 (2%) 8 (2%) Table 1: Baseline participant characteristics in the intention-to-treat 3 1 (<1%) 0 population Time between stroke onset and 99·2 (18·7) 101·2 (23·8) administration of study drug, min ICH volume, mL 16·5 (13·3) 16·9 (15·6) power <0·20 for the primary outcome). The second IVH volume, mL 1·4 (4·1) 1·7 (5·9) component was mean dierence in ICH growth between NIH Stroke Scale score 13 (8–17) 13 (8–17) both treatment groups, with the 95% upper confidence Baseline Glasgow Coma Scale score bound for the observed dierence in ICH growth 8 5 (2%) 8 (2%) exceeding that for a mean dierence of –2·5 mL less 9 8 (3%) 10 (3%) growth in the intervention group than in the control 10 15 (5%) 14 (4%) group, as predicted for this subgroup of patients from 11 21 (7%) 19 (6%) the FAST trial.3 This analysis occurred after 200 randomly 12 11 (4%) 15 (5%) assigned participants had completed 6 months of follow- 13 29 (10%) 24 (7%) up, and the DSMB recommended continuation of the 14 69 (23%) 50 (15%) trial. 15 140 (47%) 188 (57%) The second planned interim analysis, performed after (Table 1 continues in next column) approximately 430 participants had completed their 180-day assessment, was subsequently expanded. An alpha spending function with O’Brien–Fleming type for multiple comparisons. Additional prespecified stopping boundaries (two-sided) was used to stop the subgroup analyses are detailed in the statistical analysis trial for overwhelming superiority of either group, while plan (appendix 1 pp 29−31) and study protocol (appendix 2 maintaining the two-sided type 1 error rate at 0·05. The pp 21−22). trial could also be stopped early for futility if the At the beginning of enrolment, the study protocol had a conditional power was less than 0·20. Additionally, at planned analysis for futility and overwhelming ecacy the second interim analysis, we prespecified the after approximately 430 participants (half of the planned following two adaptations: an adaptive re-estimation of study sample population of 860 participants) had the study population up to a maximum of 1330 patients completed their 180-day assessment. An additional when the interim results were promising,16 and an interim analysis was subsequently added for futility adaptive population enrichment of an age-defined alone and had two components that had to be met. The subgroup (aged ≤70 years).17 Both adaptations were first component was clinical functional outcome, as defined with the promising zone approach.16,17 A measured by the mRS at 180 days (conditional simulation report conducted before the first interim Articles analysis showed that type I and type II errors were enrichment to the age group 70 years and younger controlled. showed no evidence of benefit (conditional power <1%). At this point, we had randomly assigned 626 participants Role of the funding source between Dec 3, 2021, and Oct 1, 2025 (figure 1; appendix 1 The funders of the study had no role in study design, p 11). After all 626 participants had completed their data collection, data analysis, data interpretation, or 180-day evaluation, the database was locked on writing of the report, except for the scientific programme July 25, 2025. All 626 randomly assigned participants ocer from the NINDS, who was a member of the were included in the intention-to-treat analyses executive committee of the trial. (298 [48%] in the placebo group and 328 [52%] in the intervention group); 594 participants were included in Results the per-protocol analyses (286 [48%] in the placebo group On Jan 9, 2025, the NINDS and DSMB recommended and 308 [52%] in the intervention group; figure 1). that enrolment stop for overall futility based on the 216 (35%) participants were female and 410 (65%) were interim analysis of 434 participants who had completed male, with a mean age of 61 years (SD 12) at baseline. the evaluation at 180 days (conditional power <1% under Overall, mean ICH volume was 16·7 mL (SD 14·6) and the current trend). Additionally, the prespecified mean IVH volume was 1·5 mL (SD 5·1), median NIH Placebo group Intervention group OR (95% CI)* Two-sided p value Primary outcome mRS at 180 days in the intention-to-treat population 0–2 134/298 (45%) 151/328 (46%) 1·09 (0·79 to 1·51) 0·61 3 76/298 (26%) 80/328 (24%) ·· ·· 4–6 88/298 (30%) 97/328 (30%) ·· ·· mRS at 180 days in the per-protocol population 0–2 129/286 (45%) 146/308 (47%) 1·12 (0·80 to 1·56) 0·87 3 75/286 (26%) 79/308 (26%) ·· ·· 4–6 82/286 (29%) 83/308 (27%) ·· ·· Secondary outcomes Ordinal distribution of the mRS at 90 days 0–2 113/298 (38%) 132/328 (40%) 1·13 (0·82 to 1·56) 0·87 3 57/298 (19%) 59/328 (18%) ·· ·· 4–6 128/298 (43%) 137/328 (42%) ·· ·· Ordinal distribution of the mRS at 90 days† 3 (2 to 4) 3 (2 to 4) 1·13 (0·86 to 1·51) 0·87 Ordinal distribution of the mRS at 180 days† 3 (2 to 4) 3 (2 to 4) 1·10 (0·83 to 1·47) 0·87 mRS 0–2 at 90 days 113/298 (38%) 132/328 (40%) 1·15 (0·80 to 1·66) 0·87 mRS 0–2 at 180 days 134/298 (45%) 151/328 (46%) 1·12 (0·77 to 1·61) 0·87 Utility-weighted mRs at 90 days 5·5 (2·9) 5·5 (3·0) ·· ·· OR (95% CI) 4·78 (4·20 to 5·35) 4·97 (4·40 to 5·53) ·· 0·87 Utility-weighted mRs at 180 days 6·1 (2·9) 6·1 (2·9) ·· ·· OR (95% CI) 5·27 (4·71 to 5·8) 5·40 (4·86 to 5·94) ·· 0·87 Change in ICH volume from baseline to 24 h, mL 5·5 (13·7) 1·9 (7·0) ·· ·· OR (95% CI) 4·76 (2·31 to 7·21) 1·0 (–1·39 to 3·38) ·· 0·0011 Change in ICH plus IVH volume from baseline to 24 h, mL 7·4 (19·6) 2·2 (8·4) ·· ·· OR (95% CI) 7·41 (4·02 to 10·78) 1·99 (–1·31 to 5·28) ·· 0·0011 EQ-5D at 90 days 0·5 (0·4) 0·5 (0·4) ·· 0·87 OR (95% CI) 0·40 (0·32 to 0·48) 0·40 (0·33 to 0·48) ·· ·· EQ-5D at 180 days 0·5 (0·4) 0·5 (0·5) ·· 0·87 OR (95% CI) 0·47 (0·39 to 0·54) 0·47 (0·39 to 0·54) ·· ·· Data are n (%), median (IQR), or mean (SD), unless otherwise indicated. The imputed dataset included 626 participants. mRS at day 180 was missing for ten participants; data were imputed using multiple imputation. mRS was missing for seven participants at day 30 and for 15 participants at day 90; data were imputed using hot-deck imputation. OR=odds ratio. mRS=modified Rankin Scale. ICH=intracerebral haemorrhage. IVH=intraventricular haemorrhage. EQ-5D=EQ-5D health-related quality of life. *Adjusted common ORs and 95% CIs from a proportional odds regression model are provided for categorical outcomes; least squared means and 95% CIs from a linear regression model are reported for numerical outcomes. Both regression analyses are adjusted for age, baseline ICH volume, baseline IVH volume, and pre-stroke mRS. p values for secondary outcomes were calculated with Hochberg’s step-up procedure to adjust for multiple comparisons. †All seven steps of the mRS. Table 2: Efficacy outcomes after missing data imputation 778 Articles Stroke Scale was 13 (IQR 8–17), and mean time from administration, of whom 148 (29%) had a spot sign. stroke onset to administration of study drug was 100 min Prespecified subgroup analyses of the primary outcome (SD 22; table 1). The use of emergency consent favoured recombinant factor VIIa over placebo for procedures by country is provided in appendix 1 (p 12). patients with a spot sign (adjusted common OR 1·86 Among the 626 participants, 615 (98%) completed the [95% CI 0·94–3·68]) and for those treated within 90 min mRS assessment at 180 days, four (<1%) withdrew (1·82 [0·94–3·68]), although these eects were not consent, and seven (1%) completed either a 30-day or significant (figure 2). In tertiary and exploratory analyses, 90-day follow-up visit but were lost to follow-up before the positive signals in mRS were more apparent at the 180-day assessment. Blood pressure control was 90 days among both patients with a spot sign similar between the two treatment groups (appendix 1 (2·52 [1·20–5·28]) and those treated within 90 min p 13). (2·66 [1·43–4·96]). Logistic regression interaction There was no dierential eect in the primary clinical modelling in the exploratory analyses suggested that the outcome measure of mRS at 180 days between the greatest potential benefit of recombinant factor VIIa was intervention group and placebo group (adjusted common in patients who had both a spot sign on CT angiography odds ratio [OR] 1·09 [95% CI 0·79–1·51]; p=0·61; table 2; and treatment within 90 min (appendix 1 pp 15–16). appendix 1 p 8). No dierential eects were found in the Compared with placebo, recombinant factor VIIa was secondary outcome of mRS at 90 days (1·13 [0·82–1·56]; associated with decreased growth of ICH (–3·7 mL p=0·87; table 2; appendix 1 p 8), nor in patients aged [95% CI –5·4 to –1·9]) and of ICH plus IVH growth 70 years or younger (1·09 [0·75–1·59]; appendix 1 (–5·2 mL [–7·6 to –2·8]) between baseline and follow-up pp 9, 14–16). Overall, compared with placebo, recombinant CT scan at 24 h after treatment administration. factor VIIa was associated with significantly decreased Furthermore, recombinant factor VIIa was associated growth of ICH (–3·68 mL [95% CI –5·40 to –1·94; with a substantial decrease in ICH growth (–9·4 mL) and p=0·0011) and of ICH plus IVH (–5·23 [–7·64 to –2·82]; in ICH plus IVH growth (–14·1 mL) in participants with p=0·0011) between baseline and CT scan of the head at a spot sign, compared with a small decrease in those 24 h after administration (table 2). Categories of absolute without a spot sign on CT angiography (ICH growth volume of haemorrhage growth for both treatment –2·1 mL and ICH plus IVH growth –2·7 mL; appendix 1 groups are presented in appendix 1 (p 17).8 p 17). Treatment with recombinant factor VIIa within The primary safety outcome of life-threatening 90 min was also associated with a greater decrease in thromboembolic complications within 4 days of treatment ICH plus IVH growth (–7·5 mL [95% CI –11·9 to –3·3]) administration occurred in 15 (<5%) participants in the than was placebo. Decreases in the absolute growth of intervention group and in four (1%) of those in the ICH associated with recombinant factor VIIa in patients placebo group (relative risk 3·41 [95% CI 1·14–10·15]; with a spot sign and those treated within 90 min were two-sided Fisher’s exact test p=0·020; table 3). The considered either moderate (6·1–12·5 mL) or major secondary safety outcome of life-threatening (>12·5 mL; appendix 1 pp 18–19). thromboembolic complications within 90 days occurred in 21 (6%) participants in the intervention group and in Discussion 11 (4%) in the placebo group (1·73 [0·85–3·54]; p=0·15). This multicentre, double-blind, randomised, placebo- Among all 626 participants, 511 (82%) had a baseline controlled, adaptive phase 3 trial showed that CT angiography either before or after study drug recombinant factor VIIa administered within 2 h of Placebo group Intervention group Relative risk (n=298) (n=328) (95% CI) Life-threatening thromboembolic complications within 4 days* 4 (1%) 15 (<5%) 3·41 (1·14–10·15) Life-threatening thromboembolic complications within 90 days*† 11 (4%) 21 (6%) 1·73 (0·85–3·54) Unstable angina 0 0 ·· Deep venous thrombosis (not leading to pulmonary embolism) 4 (1%) 7 (2%) 1·59 (0·47–5·38) Mortality within 180 days 22 (7%) 20 (6%) 0·83 (0·46–1·48) mRS 5–6 at 180 days 31 (10%) 37 (11%) 1·08 (0·69–1·70) Myocardial injury without acute coronary syndrome 30 (10%) 49 (15%) 1·48 (0·97–2·27) Acute myocardial infarction‡ 4 (1%) 3 (1%) 0·68 (0·15–3·02) Acute cerebral infarction‡ 11 (4%) 18 (5%) 1·49 (0·71–3·10) Acute pulmonary embolism‡ 3 (1%) 5 (2%) 1·51 (0·37–6·28) mRS=modified Rankin Scale. *Defined as a serious adverse event of acute myocardial infarction, acute cerebral infarction, or acute pulmonary embolism. †One life- threatening thromboembolic complication event occurred 97 days after randomisation in the placebo group and was excluded from the secondary safety outcome of life- threatening thromboembolic complications within 90 days. ‡Serious and non-serious adverse events, including small diffusion-positive lesions without any clinical change. Table 3: Safety outcomes in the intention-to-treat population Articles Placebo Recombinant factor VIIa OR (95% CI) Age (years) ≤70 232 241 1·10 (0·76–1·59) >70 66 87 1·10 (0·57–2·14) Country or region USA 78 95 0·80 (0·43–1·47) Japan 132 144 1·40 (0·86–2·29) Canada 47 34 1·09 (0·45–2·67) Europe 41 55 0·94 (0·39–2·29) Time since last known well (min) <90 92 82 1·82 (0·98–3·40) ≥90 206 246 0·90 (0·62–1·32) Ultra-early haematoma growth (mL/h) <10 128 153 0·90 (0·55–1·46) ≥10 170 175 1·25 (0·81–1·92) Baseline ICH volume (mL) <31 253 278 1·12 (0·79–1·58) ≥31 45 50 0·95 (0·38–2·35) Spot sign on CT angiography Absence 174 183 0·87 (0·57–1·34) Presence (≥1) 77 71 1·86 (0·94–3·68) Sex Male 193 217 1·30 (0·87–1·95) Female 105 111 0·79 (0·46–1·36) Race Asian 169 173 1·27 (0·82–1·97) Black or African American 23 30 0·60 (0·19–1·84) White 100 118 0·83 (0·48–1·45) Ethnicity Hispanic or Latinx 25 32 0·82 (0·29–2·34) Not Hispanic or Latinx 271 296 1·11 (0·78–1·56) Overall 298 328 1·09 (0·79–1·51) 0·5 1·0 2·0 3·0 4·0 OR (95% CI) Favours placebo Favours intervention Figure 2: Prespecified subgroup analyses of mRS at 180 days mRS=modified Rankin Scale. OR=odds ratio. ICH=intracerebral haemorrhage. symptom onset did not improve functional outcomes in in participants with a spot sign and in those who were patients with spontaneous ICH compared with placebo. treated within 90 min is the largest observed with any Additionally, this agent was associated with a small medical therapy for spontaneous ICH to date. but significantly increased risk of life-threatening Medical and surgical trials for ICH have shown potential thromboembolic complications. This risk was found benefit for some subsets of patients, but illustrate even though recombinant factor VIIa decreased the remaining challenges.18 These challenges include selecting volume of haemorrhage expansion by a mean 3·5 mL subgroups most likely to benefit from treatment, overall, which is consistent with previous trials of this minimising time to treatment, and reducing a sucient agent and is a greater decrease than other reported volume of ICH to improve functional outcomes. The haemostatic trials for patients with ICH. The FASTEST ENRICH trial of minimally invasive surgery within 24 h of trial shows that the greatest decrease in ICH growth onset showed improved outcomes for patients with lobar occurred in participants with a spot sign and in those ICH, but not basal ganglia ICH.19 The study’s findings who were treated within 90 min. Additionally, this study were not substantiated by the MIND trial, which had a suggests that the mean volume of decreased haemorrhage treatment window of 72 h.20 Three trials of early blood growth that is necessary to improve functional outcomes pressure control to a target of 140 mm Hg systolic is likely not 3–4 mL, but at least 6–12 mL. Larger volumes suggested mild to modest improvements in functional of haematoma expansion have been linked to an outcomes.21–23 However, none of these studies clearly increased likelihood of poor outcomes.8 To our slowed intracranial bleeding, except for the Chinese knowledge, the reduction in haematoma growth observed INTERACT4 trial, in which patients with potential stroke 780 Articles and a blood pressure of at least 150 mm Hg in the angiography as a biological marker of substantial ambulance were randomly assigned to either intravenous ongoing bleeding is strongly related to the timing of CT urapidil or standard care before brain imaging.23 The trial angiography and how quickly recombinant factor VIIa or showed neutral results overall, with worse clinical other haemostatic agents need to be administered after outcomes in patients with ischaemic stroke but identification of a spot sign. This finding is supported by significantly improved outcomes in those with ICH. the results of other haemostatic trials of tranexamic acid Several haemostatic trials reported a slowing of bleeding for patients with spontaneous ICH, which showed that with reversal of anticoagulation in patients with ICH the only signal for slowing of intracranial bleeding was in while on vitamin K antagonists or factor Xa or thrombin participants who had a spot sign on CT angiography and inhibitors; however, none of these trials showed signifi- were treated within 2 h.29,30 cant improvements in clinical outcomes.24,25 Previous Exception from informed consent and emergency prospective studies exploring the relationship between consent procedures, the use of mobile stroke units, and decreased haemorrhage expansion in patients with ICH emphasising time to treatment in the standard workflow and improved clinical outcomes on the mRS suggest that of patients with stroke all had a role in the rapid a mean decrease in the volume of ICH of 3–4 mL due to a administration of study treatment in the FASTEST trial, haemostatic agent is likely the minimum volume needed even with the requirement of brain imaging.9 FASTEST to detect a clinical benefit in a trial.7,8 Nevertheless, the is the largest trial treating patients with stroke within 2 h clinical benefit from this amount of haemostasis must of onset that requires brain imaging before treatment, outweigh the increase in life-threatening thromboembolic including trials of ischaemic stroke, which is more than complications associated with haemostatic agents, which two times more common globally31 and approximately can also aect clinical outcomes.1 eight times more common in the USA.32 FASTEST also CT angiography as a standard diagnostic test for the reflects the importance of global trials to enrol a sucient evaluation of acute stroke accelerated after the study population of a less common type of stroke, demonstrated ecacy of endovascular therapy for one that is more common in Asian countries.33 Given patients with ischaemic stroke in 2015 and the that only about 45% of participants in FASTEST received subsequent importance of identifying vascular occlusions treatment within 90 min or had a spot sign identified and minimising time to treatment.26 This clinical within 2 h, the ongoing extension of this trial (FASTEST development led to the routine assessment of more part 2; NCT07227246) is recruiting from additional sites; patients with ICH, because CT angiography has become therefore, recruitment will be correspondingly slower. part of the normal workflow for the assessment of The step-forward randomisation process in the patients with potential stroke in high-income countries, FASTEST trial, identical to that in the NINDS rt-PA Stroke generating additional evidence that a spot sign represents Trial,34,35 allowed for rapid participant enrolment and a marker of ongoing bleeding. However, the predictive minimisation of time to treatment. This process was value of the spot sign of clinically significant haematoma crucial in FASTEST, but cannot adjust for the potential growth in patients with ICH substantially diminishes imbalances in the number of participants in each with time. In a pooled patient-level data analysis of treatment group nor minimisation of key baseline 12 studies exploring the relationship between the variables that are known to be related to outcomes after presence of a spot sign and ICH growth in 1038 patients, ICH. Adjustment for imbalances in these key variables can Dowlatshahi and colleagues12 reported a significant only occur at the time of analysis, which was planned for decrease in haematoma expansion as time between in our statistical approach. symptom onset and CT angiography increased in At the time that the DSMB recommended halting the patients with a spot sign (p=0·004), with positive trial for futility in its current iteration, the board also predictive values decreasing from 53% to 33%. recommended consideration to continue the trial within Two small pilot randomised trials of recombinant the subgroup of patients with a spot sign. We factor VIIa in patients with ICH and a spot sign treated subsequently added treatment within 90 min to this only four participants within 2 h of onset, and had subgroup when the full FASTEST database was available substantial delays between baseline CT angiography and for analysis. However, a limitation of our results is that administration of the intervention.27 These trials did not the proportion of patients with ICH worldwide who show any clear slowing of bleeding with recombinant might benefit from recombinant factor VIIa would be factor VIIa. In one of these spot sign studies, an small if treatment is eective only for these subgroups. immediate post-dose CT was performed to evaluate what We estimate that approximately 5% of the proportion of bleeding might have occurred before the 1 840 500 patients with ICH globally would qualify for study drug could be administered. This analysis revealed recombinant factor VIIa treatment with a spot sign that 90% of all haematoma expansion had occurred within 2 h or treatment within 90 min without a spot between baseline CT and post-dose CT, suggesting that sign.36 This trial’s focus on rapid treatment by minimising much faster study drug administration is needed.28 These time to evaluation and treatment and emergency consent results and our data suggest that the usefulness of CT procedures can be replicated in sites with CT angiography Articles and processes that minimise time to imaging and related to the manuscript; royalties from Cambridge University Press for treatment. Demonstrating eective haemostatic a handbook on neurocritical care; and honoraria for educational activities from the Society of Critical Care Medicine, outside of the treatment for ICH, even in a smaller proportion of submitted work. KT reports research support from the Japan Agency for patients, is likely to expand the number of eligible Medical Research and Development (JP19lk0201094 and JP23lk0221171); patients in the future with advances in imaging and grants and contracts from SoftBank Group; consulting fees from Janssen recognition, as also occurred with access to thrombolysis Pharmaceuticals; and honoraria for lectures from Otsuka Pharmaceutical, outside of the submitted work. DD reports funding treatment for ischaemic stroke. Only 1% of patients with from the Canadian Institutes of Health Research for the ICATCHER ischaemic stroke were treated with thrombolytics in the trial. DD also holds a patent for an algorithm for the automatic years immediately following its approval by the US Food recognition of contrast extravasation, outside of the submitted work. and Drug Administration in 1995, which increased to AMD reports consulting fees from AstraZeneca; honoraria for continuing medical education events from Novo Nordisk and 7% in the USA by 201437 and to 21% in Norway in 2021.38 AstraZeneca; participation on a DSMB for the TRUST study (Philips); Subgroup analyses, even when prespecified as in the leadership roles as Chair of the Board of Directors of the Canadian current trial, have limitations of a smaller sample size, Stroke Consortium; and stock ownership in Circle CVI, outside of the limited power, and multiple statistical testing, and are submitted work. SP reports grants or contracts from BMS–Pfizer (ATTICUS trial), Boehringer Ingelheim (non-financial support for the more subject to findings due to chance alone. The linkage REVISION trial), Daiichi Sankyo, the German Federal Joint Committee between much larger decreases in haemorrhage expansion Innovation Fund, the German Federal Ministry of Education and in the two subgroups with signals of clinical ecacy Research, Helena Laboratories, Werfen, and the European Union provides a good biological rationale that these observations Horizon 2020 programme; consulting fees from Alexion, AstraZeneca, Daiichi Sankyo, and Werfen; honoraria from Alexion, Bayer, Boehringer were not due to chance; however, this requires further Ingelheim, BMS–Pfizer, and Portola; and participation on a DSMB for testing in the ongoing FASTEST 2 trial (NCT07227246). the OPENS-2 trial, outside of the submitted work. HJA reports grants In conclusion, recombinant factor VIIa administered from the German Federal Ministry of Education and Research, the within 2 h of ICH onset slowed haematoma growth, but German Research Foundation, and German Innovation Funds; consulting fees from Eli Lilly and Boehringer Ingelheim; honoraria from did not improve functional outcomes at 180 days in Boehringer Ingelheim, Pfizer, BMS, Novartis, Ever Neuropharma, and patients with spontaneous ICH. Additionally, this agent Bayer Healthcare; and participation on an advisory board and DSMB for was associated with a small increased risk of life- Novo Nordisk, outside of the submitted work. PMB reports grants from threatening thromboembolic complications. Further the NIHR Health Technology Assessment programme (PhEAST trial) and the Alzheimer’s Society (CVD-Cog trial); consulting roles with testing of recombinant factor VIIa in patients with the CoMind and DiaMedica; chairing the AVERT-DOSE DSMB; leadership greatest risk of continued bleeding is ongoing. roles with the World Stroke Organisation; stock or advisory interests in CoMind and DiaMedica; and receipt of equipment and training from Contributors Phagenesis, outside of the submitted work. TO reports honoraria for JPB, JCG, and AMN conceived and designed the study and provided lectures or participation in speakers bureaus from Daiichi Sankyo, overall scientific oversight. The trial’s executive committee, including Otsuka Pharmaceutical, Takeda, AstraZeneca, Kowa, Takeda KT, DD, TS, CM, PMB, AMD, PK, HJA, AV, SY, SAM, LLW, JDM, RA, Pharmaceutical Company, and Nestlé Japan, outside of the submitted and ID, contributed to trial governance and supervised study conduct work. MF-D reports institutional grant support from the Japan Agency across participating sites. SAM served as the independent medical safety for Medical Research and Development (JP22oa0310011 monitor for the study. JJE developed the statistical analysis plan and led and JP25oa0439003) and JSPS KAKENHI (21K17241), outside of the the statistical analyses, with analytical support from JB and AP and input submitted work. All other authors declare no competing interests. from the study investigators. Imaging data were centrally reviewed and adjudicated by the FASTEST Imaging Core Laboratory (LLW, AV, and Data sharing JCG). ThH and RA developed and maintained imaging training and the Upon completion of the trial and the dissemination of primary results, certification platform for participating sites. ES, SAQ, and JPB led trial de-identified patient-level data (analysis data files) will be made available operations, project administration, data curation, validation, and to the wider scientific community via the NINDS data repository. regulatory and site coordination in the USA, and oversaw global eorts Acknowledgments in other countries. KT, SY, MK, and MF-D oversaw trial operations in The FASTEST trial is funded by NINDS and the Japan Agency for Japan. DD oversaw trial operations in Canada. TS, PMB, and CM Medical Research and Development. The trial infrastructure for oversaw trial operations in Germany, Spain, and the UK. NooS oversaw FASTEST in the USA was also supported by the NINDS through NIH investigational product supply, international drug shipment, and StrokeNet. Novo Nordisk supplied the study medication and monies to pharmacy coordination. Site investigators NobS, TO, MY, TaH, NaS, KM, support temperature monitoring and enrolment of participants outside MYDT, CDS, FM, YS, YN, TG, C-HS, TeH, SP, TI, MI, BB, KBW, and IS, of business hours. together with the FASTEST Investigators, enrolled participants and conducted study procedures at their respective sites. All authors References contributed to interpretation of the data, critically reviewed and edited 1 Broderick JP, Grotta JC, Naidech AM, et al. The story of the manuscript, approved the final version, and agreed to be accountable intracerebral hemorrhage: from recalcitrant to treatable disease. for the work. JJE, AP, and JPB verified the data. All authors had full Stroke 2021; 52: 1905–14. access to all the data in the study and had final responsibility for the 2 Mayer SA, Brun NC, Begtrup K, et al, and the Recombinant decision to submit for publication. Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Recombinant activated factor VII for acute intracerebral Declaration of interests hemorrhage. N Engl J Med 2005; 352: 777–85. JPB reports funding from NINDS as the primary funder of the trial to 3 Mayer SA, Brun NC, Begtrup K, et al, and the FAST Trial the University of Cincinnati; and receipt of study medication and Investigators. Ecacy and safety of recombinant activated factor VII financial support from Novo Nordisk for temperature monitoring of for acute intracerebral hemorrhage. N Engl J Med 2008; 358: 2127–37. study medication and support for investigator eorts outside business 4 Mayer SA, Davis SM, Skolnick BE, et al, and the FAST trial hours. JPB also reports consulting fees related to a Roche paediatric investigators. Can a subset of intracerebral hemorrhage patients stroke trial and consultation for Basking Bioscience, outside of the benefit from hemostatic therapy with recombinant activated submitted work. 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